Hepatic danger signaling triggers TREM2+ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation.

Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is an advanced stage of metabolic fatty liver disease. The pathogenic mechanisms of MASH center on hepatocyte injury and the ensuing immune response within the liver microenvironment. Recent work has implicated TREM2+ macrophages in various disease conditions, and substantial induction of TREM2+ NASH-associated macrophages (NAMs) serves as a hallmark of metabolic liver disease. Despite this, the mechanisms through which NAMs contribute to MASH pathogenesis remain poorly understood. Here, we identify membrane-spanning 4-domains a7 (MS4A7) as a NAM-specific pathogenic factor that exacerbates MASH progression in mice. Hepatic MS4A7 expression was strongly induced in mouse and human MASH and associated with the severity of liver injury. Whole-body and myeloid-specific ablation of Ms4a7 alleviated diet-induced MASH pathologies in male mice. We demonstrate that exposure to lipid droplets (LDs), released upon injury of steatotic hepatocytes, triggered NAM induction and exacerbated MASH-associated liver injury in an MS4A7-dependent manner. Mechanistically, MS4A7 drove NLRP3 inflammasome activation via direct physical interaction and shaped disease-associated cell states within the liver microenvironment. This work reveals the LD-MS4A7-NLRP3 inflammasome axis as a pathogenic driver of MASH progression and provides insights into the role of TREM2+ macrophages in disease pathogenesis.

Antibacterial activity and improvement of the oxidative stability of soybean oil by 4-hydroxybenzyl isothiocyanate from white mustard seeds.

4-Hydroxybenzyl isothiocyanate (4-HBITC) is one of the most important secondary metabolite products in white mustard seeds. The antibacterial activity and inhibition of lipid oxidation of 4-HBITC were investigated. The results indicated that 4-HBITC had a significant antibacterial effect on Escherichia coli, Staphylococcus aureus, and Salmonella typhimurium, and its effect on gram-positive bacteria was superior to that on gram-negative bacteria. The combination of 4-HBITC with citric acid or ascorbic acid had a better antibacterial effect than adding them alone. The antibacterial mechanism of 4-HBITC to affect the metabolic activity rather than the integrity or the permeability of cell membranes was identified. In addition, white mustard seed extract which contains 4-HBITC was found to extend the oxidative stability of soybean oil, and this effect was also improved after the combination of 4-HBITC with citric acid. These results indicated that 4-HBITC and white mustard seed extract have potential for application as a natural preservatives in food and for improving the oxidative stability of edible oils.

Hepatic mitochondrial NAD + transporter SLC25A47 activates AMPKα mediating lipid metabolism and tumorigenesis.

BACKGROUND AIMS: SLC25A47 was initially identified as a mitochondrial HCC-downregulated carrier protein, but its physiological functions and transport substrates are unknown. We aimed to investigate the physiological role of SLC25A47 in hepatic metabolism. APPROACH RESULTS: In the treatment of hepatocytes with metformin, we found that metformin can transcriptionally activate the expression of Slc25a47 , which is required for AMP-activated protein kinase α (AMPKα) phosphorylation. Slc25a47 -deficient mice had increased hepatic lipid content, triglycerides, and cholesterol levels, and we found that Slc25a47 deficiency suppressed AMPKα phosphorylation and led to an increased accumulation of nuclear SREBPs, with elevated fatty acid and cholesterol biosynthetic activities. Conversely, when Slc25a47 was overexpressed in mouse liver, AMPKα was activated and resulted in the inhibition of lipogenesis. Moreover, using a diethylnitrosamine-induced mouse HCC model, we found that the deletion of Slc25a47 promoted HCC tumorigenesis and development through the activated mammalian target of rapamycin cascade. Employing homology modeling of SLC25A47 and virtual screening of the human metabolome database, we demonstrated that NAD + was an endogenous substrate for SLC25A47, and the activity of NAD + -dependent sirtuin 3 declined in Slc25a47 -deficient mice, followed by inactivation of AMPKα. CONCLUSIONS: Our findings reveal that SLC25A47, a hepatocyte-specific mitochondrial NAD + transporter, is one of the pharmacological targets of metformin and regulates lipid homeostasis through AMPKα, and may serve as a potential drug target for treating NAFLD and HCC.

Neuregulin 4 suppresses NASH-HCC development by restraining tumor-prone liver microenvironment.

The mammalian liver comprises heterogeneous cell types within its tissue microenvironment that undergo pathophysiological reprogramming in disease states, such as non-alcoholic steatohepatitis (NASH). Patients with NASH are at an increased risk for the development of hepatocellular carcinoma (HCC). However, the molecular and cellular nature of liver microenvironment remodeling that links NASH to liver carcinogenesis remains obscure. Here, we show that diet-induced NASH is characterized by the induction of tumor-associated macrophage (TAM)-like macrophages and exhaustion of cytotoxic CD8+ T cells in the liver. The adipocyte-derived endocrine factor Neuregulin 4 (NRG4) serves as a hormonal checkpoint that restrains this pathological reprogramming during NASH. NRG4 deficiency exacerbated the induction of tumor-prone liver immune microenvironment and NASH-related HCC, whereas transgenic NRG4 overexpression elicited protective effects in mice. In a therapeutic setting, recombinant NRG4-Fc fusion protein exhibited remarkable potency in suppressing HCC and prolonged survival in the treated mice. These findings pave the way for therapeutic intervention of liver cancer by targeting the NRG4 hormonal checkpoint.

Effect of Emulsion Particle Size on the Encapsulation Behavior and Oxidative Stability of Spray Microencapsulated Sweet Orange Oil (Citrus aurantium var. dulcis).

Three different feed emulsions of different particle sizes were mixed with a modified starch and maltodextrin and spray dried to make a large (LP), small (SP), and nano-size encapsulated powder (NP), respectively. Emulsion size, oil content, loading capacity (LC), encapsulation efficiency (EE), water content, aw, scanning electron microscopy (SEM), glass transition temperature (Tg), as well as d-limonene release characteristic and limonene oxide formation rate during 37 °C and various aw storage were determined. With the increase of the feed emulsion size, the reconstituted emulsion size of the LP tended to increase and change to a bimodal distribution. The surface oil content increased with the increasing size of the reconstituted emulsion, and the opposite was true for EE. The smaller the reconstituted emulsion size, the higher Tg during a low aw condition. The Tg of the LP, SP and NP were 62, 88, and 100 °C, respectively, and NP > SP > LP. The release and the oxidative rate of d-limonene was the lowest for the NP and then increased for the SP and LP. The release and oxidative rates increased with the elevation of aw and peaked at 0.33. The powder surface morphological structure was intact, the spray-dried powder was more stable, and microstructure changed from a glass state to a rubbery state during storage.

Light-Driven Intramolecular C-N Cross-Coupling via a Long-Lived Photoactive Photoisomer Complex.

Reported herein is a visible-light-driven intramolecular C-N cross-coupling reaction under mild reaction conditions (metal- and photocatalyst-free, at room temperature) via a long-lived photoactive photoisomer complex. This strategy was used to rapidly prepare the N-substituted polycyclic quinazolinone derivatives with a broad substrate scope (>50 examples) and further exploited to synthesize the natural products tryptanthrin, rutaecarpine, and their analogues. The success of gram-scale synthesis and solar-driven transformation, as well as promising tumor-suppressing biological activity, proves the potential of this strategy for practical applications. Mechanistic investigations, including control experiments, DFT calculations, UV-vis spectroscopy, EPR, and X-ray single-crystal structure of the key intermediate, provides insight into the mechanism.

Organic cation transporter 3 (Oct3) is a distinct catecholamines clearance route in adipocytes mediating the beiging of white adipose tissue.

Beiging of white adipose tissue (WAT) is a particularly appealing target for therapeutics in the treatment of metabolic diseases through norepinephrine (NE)-mediated signaling pathways. Although previous studies report NE clearance mechanisms via SLC6A2 on sympathetic neurons or proinflammatory macrophages in adipose tissues (ATs), the low catecholamine clearance capacity of SLC6A2 may limit the cleaning efficiency. Here, we report that mouse organic cation transporter 3 (Oct3; Slc22a3) is highly expressed in WAT and displays the greatest uptake rate of NE as a selective non-neural route of NE clearance in white adipocytes, which differs from other known routes such as adjacent neurons or macrophages. We further show that adipocytes express high levels of NE degradation enzymes Maoa, Maob, and Comt, providing the molecular basis on NE clearance by adipocytes together with its reuptake transporter Oct3. Under NE administration, ablation of Oct3 induces higher body temperature, thermogenesis, and lipolysis compared with littermate controls. After prolonged cold challenge, inguinal WAT (ingWAT) in adipose-specific Oct3-deficient mice shows much stronger browning characteristics and significantly elevated expression of thermogenic and mitochondrial biogenesis genes than in littermate controls, and this response involves enhanced ß-adrenergic receptor (ß-AR)/protein kinase A (PKA)/cyclic adenosine monophosphate (cAMP)-responsive element binding protein (Creb) pathway activation. Glycolytic genes are reprogrammed to significantly higher levels to compensate for the loss of ATP production in adipose-specific Oct3 knockout (KO) mice, indicating the fundamental role of glucose metabolism during beiging. Inhibition of ß-AR largely abolishes the higher lipolytic and thermogenic activities in Oct3-deficient ingWAT, indicating the NE overload in the vicinity of adipocytes in Oct3 KO adipocytes. Of note, reduced functional alleles in human OCT3 are also identified to be associated with increased basal metabolic rate (BMR). Collectively, our results demonstrate that Oct3 governs ß-AR activity as a NE recycling transporter in white adipocytes, offering potential therapeutic applications for metabolic disorders.

The SLC transporter in nutrient and metabolic sensing, regulation, and drug development.

The prevalence of metabolic diseases is growing worldwide. Accumulating evidence suggests that solute carrier (SLC) transporters contribute to the etiology of various metabolic diseases. Consistent with metabolic characteristics, the top five organs in which SLC transporters are highly expressed are the kidney, brain, liver, gut, and heart. We aim to understand the molecular mechanisms of important SLC transporter-mediated physiological processes and their potentials as drug targets. SLC transporters serve as 'metabolic gate' of cells and mediate the transport of a wide range of essential nutrients and metabolites such as glucose, amino acids, vitamins, neurotransmitters, and inorganic/metal ions. Gene-modified animal models have demonstrated that SLC transporters participate in many important physiological functions including nutrient supply, metabolic transformation, energy homeostasis, tissue development, oxidative stress, host defense, and neurological regulation. Furthermore, the human genomic studies have identified that SLC transporters are susceptible or causative genes in various diseases like cancer, metabolic disease, cardiovascular disease, immunological disorders, and neurological dysfunction. Importantly, a number of SLC transporters have been successfully targeted for drug developments. This review will focus on the current understanding of SLCs in regulating physiology, nutrient sensing and uptake, and risk of diseases.